9 to 50 cancers reduce Vitamin D receptor activation

15 Solid tumors with altered/deficient VDR

Perplexity AI Jan 2025 includes images

Breast cancer, including BRCA1‑mutated and sporadic types.[1]
Colorectal cancer (CRC), including colon adenomas, carcinoma, and colitis‑associated cancer.[1]
Non‑small cell lung carcinoma (NSCLC) and small‑cell lung cancer (noted lower VDR positivity in SCLC).[1]
Ovarian cancer.[1]
Pancreatic ductal adenocarcinoma (PDAC).[1]
Prostate cancer.[1]
Skin cutaneous melanoma.[1]
Bladder urothelial carcinoma.[1]
Esophageal adenocarcinoma.[1]
Glioblastoma multiforme.[1]
Hepatocellular carcinoma and liver cancer related to hepatic stellate cell activity.[1]
Gastric cancer.[1]
Head and neck squamous cell carcinoma (HNSCC).[1]
Oral cancer (cited in references discussing VDR in oral malignancy).[1]
Renal cell carcinoma (via miR‑125b targeting VDR).[1]

Mechanistic/indirect links via VDR loss or dysregulation

Melanoma progression through loss of VDR signaling and Wnt–β‑catenin activation.[1]
Colon and extraintestinal (breast) tumorigenesis driven by intestinal epithelial VDR deficiency and dysbiotic microbiota.[1]
Adrenal tumors (benign and malignant) with altered VDR promoter methylation.[1]
Hepatocellular carcinoma and colorectal cancer with VDR promoter hypermethylation and reduced expression.[1]

If you want a refined subset restricted to cancers where low/poor VDR activation is explicitly linked to worse prognosis (e.g., Table 1 cohorts), that can be listed separately.

[1] Study PDF, below

Many of the cancers appear to deactivate the VDR

Epigenetic silencing (promoter methylation)

Breast cancer – methylation-induced VDR silencing contributes to calcitriol resistance and reduces downstream VDR pathway effectors[1]
Colorectal cancer – promoter hypermethylation regulates VDR expression and silences the receptor[1]
Hepatocellular carcinoma – VDR gene promoter methylation documented[1]
Adrenal tumors (benign and malignant) – altered VDR promoter methylation status[1]

Transcriptional repression by oncogenic factors

Colon cancer – multiple mechanisms:
- TNF-α-driven inflammation increases Snail1/2 to suppress VDR[1]
- EGFR upregulates Snail1, downregulating VDR (forming a bidirectional negative feedback loop)[1]
- SLUG recruits co-repressors (CtBP1/HDAC1) to the VDR promoter, inhibiting expression via chromatin remodeling[1]
- Acidic tumor microenvironment inhibits VDR transcription by downregulating PPARδ and promoting VDR nuclear export[1]
- K-ras mutant cells suppress VDR transcription via p38-AP-1-dependent trans-repression[1]
Breast cancer – SLUG-mediated functional repression of the VDR gene promoter[1]
Hepatocellular carcinoma – downregulation of KLF4 (a VDR-specific transcription factor) reduces VDR expression and promotes proliferation[1]

Post-transcriptional silencing via microRNAs

Breast cancer – miR-181a-5p targets VDR[1]
Colon cancer – TNF-α-induced miR-346 reduces VDR expression, promoting colitis and carcinogenesis; lncRNA H19 overexpression reduces VDR via miR-675-5p[1]
Renal cell carcinoma – miR-125b targets VDR[1]

Genomic loss

Multiple cancers show VDR copy number loss that correlates with tumor progression, with distant metastases exhibiting lower VDR copy numbers than regional lymph node metastases[1]

Disruption of VDR signaling machinery

Prostate cancer – constitutive MAPK signaling phosphorylates RXR at Ser260, disrupting VDR-RXR heterodimer formation and impairing signaling[1]
Multiple cancers – PPARγ competes with VDR for RXR binding, blocking VDR signaling[1]

The study emphasizes that these cancer-mediated mechanisms create a "dominant negative" environment where even adequate vitamin D levels cannot activate tumor suppressor functions due to receptor silencing or dysfunction.[1]

[1] Study PDF below

50 Cancers: Perplexity AI Jan 2026

Based on comprehensive research combining the attached study with current medical literature, I've identified over 50 cancer types with documented associations to the vitamin D receptor (VDR).

Solid Tumors (40+ types)

Gastrointestinal: Colorectal cancer, gastric cancer, esophageal adenocarcinoma and squamous cell carcinoma, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, and cholangiocarcinoma[1][2][3][4][5][6]

Breast & Gynecological: All breast cancer subtypes (including BRCA1-mutated, triple-negative, and invasive ductal carcinoma), ovarian, endometrial, cervical, vulvar, and vaginal cancers[2][7][8][9][10][11][1]

Urological: Prostate cancer, bladder urothelial carcinoma, and multiple renal cell carcinoma subtypes (clear cell, papillary, chromophobe, collecting duct)[12][13][14][1][2]

Head, Neck & Respiratory: Head and neck squamous cell carcinoma (including oral), non-small cell lung cancer, lung adenocarcinoma, and small-cell lung cancer[15][16][17][18][19][1]

Skin: Cutaneous melanoma and uveal melanoma[20][21][22][23][24][1]

Brain & CNS: Glioblastoma multiforme, pediatric high-grade and low-grade gliomas[25][26][27][1]

Endocrine: Papillary thyroid carcinoma, differentiated thyroid cancer, and adrenal tumors[28][29][30][31][1]

Bone & Soft Tissue: Osteosarcoma and sarcomas[32][31]

Hematological Malignancies (10+ types)

Leukemias: Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and large granular lymphocytic leukemia[33][34][35][36][37]

Lymphomas: Diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, T-cell lymphoma, and non-Hodgkin lymphoma[38][35][37][33]

Other: Multiple myeloma, myelodysplastic syndrome, and aplastic anemia[37][39][40][33]

Cancers That Actively Deactivate VDR

The following cancers employ specific mechanisms to silence or inactivate VDR:[1]

Epigenetic silencing (promoter methylation): Breast cancer, colorectal cancer, hepatocellular carcinoma, adrenal tumors

Transcriptional repression: Colon cancer (via TNF-α→Snail1/2, EGFR→Snail1, SLUG recruitment, acidic microenvironment, K-ras mutations), hepatocellular carcinoma (KLF4 downregulation), breast cancer (SLUG-mediated)

MicroRNA-mediated silencing: Breast cancer (miR-181a-5p), colon cancer (miR-346, H19→miR-675-5p), renal cell carcinoma (miR-125b)

Genomic loss: Multiple cancers show VDR copy number deletions correlating with tumor progression and metastasis

Signaling disruption: Prostate cancer (MAPK phosphorylates RXR, disrupting VDR-RXR heterodimers), multiple cancers (PPARγ competes for RXR binding)

Clinical Significance

High VDR expression generally predicts better outcomes in breast (nuclear), colorectal, lung, melanoma, pancreatic, esophageal, and brain cancers[21][7][22][6][1]

VDR polymorphisms (FokI, BsmI, TaqI, ApaI) significantly modify cancer risk and prognosis across colorectal, prostate, breast, ovarian, gastric, renal cancers and multiple hematological malignancies[8][5][14][2][37]

Vitamin D deficiency is associated with poor prognosis in AML, CLL, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, multiple myeloma, and renal cell carcinoma, with supplementation potentially improving outcomes[13][33][38][37]

I've created a comprehensive reference document with all cancer types, mechanisms, and citations for your VitaminDWiki.com database.

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9 cancers are known to reduce activation of the vitamin D receptor (VDR)

either by lowering VDR expression, impairing ligand availability (1,25-dihydroxyvitamin D), or disrupting downstream signaling. Below is a mechanism-based, cancer-specific overview.

Chat-GPT Jan 2026

1. Colorectal Cancer: Evidence level: strong

↓ VDR expression in advanced and poorly differentiated tumors
Epigenetic silencing (promoter methylation of VDR)
Mutations or downregulation of CYP27B1 (activates vitamin D)
↑ CYP24A1, which degrades active vitamin D
Loss of vitamin D–mediated control of Wnt/β-catenin signaling

➡️ This is one of the best-established cancers showing impaired VDR signaling.

2. Breast Cancer: Evidence level: strong

Aggressive subtypes (triple-negative, HER2+) show ↓ VDR
Estrogen-independent tumors often lose VDR responsiveness
CYP24A1 overexpression common
VDR polymorphisms associated with poorer outcomes

➡️ Loss of VDR correlates with increased proliferation and metastasis.

3. Prostate Cancer: Evidence level: strong

Progressive loss of VDR during tumor advancement
Decreased responsiveness to calcitriol despite VDR presence
Increased CYP24A1 expression
Androgen signaling can suppress vitamin D signaling

➡️ Early disease may respond; late-stage disease often does not.

4. Pancreatic Ductal Adenocarcinoma: Evidence level: moderate–strong

Reduced epithelial VDR signaling
Stromal activation alters vitamin D metabolism
Functional resistance despite VDR expression
Altered RXR availability (VDR requires RXR dimerization)

➡️ Interestingly, stromal VDR activation may still be therapeutically useful.

5. Lung Cancer (especially NSCLC): Evidence level: moderate

Reduced VDR expression in poorly differentiated tumors
Smoking-associated epigenetic suppression of VDR
CYP24A1 amplification common in lung tumors

➡️ Lower VDR correlates with worse prognosis.

6. Melanoma: Evidence level: moderate

Progressive loss of VDR with tumor stage
Downregulation of nuclear VDR (cytoplasmic mislocalization)
Loss of vitamin D antiproliferative effects

➡️ Advanced melanomas often show near-complete VDR inactivity.

7. Ovarian Cancer: Evidence level: moderate

Reduced VDR expression in high-grade serous carcinoma
CYP24A1 overexpression
Impaired vitamin D–induced apoptosis

8. Hepatocellular Carcinoma (HCC): Evidence level: emerging

Chronic liver disease impairs vitamin D activation
Reduced VDR expression in tumor tissue
Disrupted bile acid–vitamin D signaling crosstalk

9. Hematologic Malignancies (Selective)

Examples: AML, CLL, some lymphomas

Functional VDR resistance despite expression
Differentiation block prevents vitamin D–mediated effects
Some leukemias respond only at supraphysiologic doses

Common Mechanisms Across These Cancers

Mechanism	Effect
↓ VDR expression	Reduced transcriptional response
↑ CYP24A1	Rapid degradation of active vitamin D
↓ CYP27B1	Reduced local vitamin D activation
Epigenetic silencing	Loss of tumor suppressor effects
RXR disruption	Prevents VDR signaling
Nuclear exclusion of VDR	Functional inactivation

Important Distinction

Low serum vitamin D ≠ impaired VDR
Many cancers actively disable the receptor or its signaling, even when vitamin D levels are adequate.